Persistent pulmonary hypertension of the newborn: Historical perspectives

  • Steven M. Donn
    Division of Neonatal-Perinatal Medicine, Department of Pediatrics, C.S. Mott Children's Hospital, Michigan Medicine, University of Michigan, 8-621 C.S. Mott Children's Hospital, 1540 E. Hospital Drive, SPC 4254, Ann Arbor, MI, 48109-4254, USA
    Search for articles by this author
Published:February 13, 2022DOI:


      For many decades, persistent pulmonary hypertension of the newborn (PPHN) remained a baffling disorder, often confused with cyanotic congenital heart disease, with a very high mortality. Originally described as a condition characterized by clear lung fields and profound hypoxemia, modern diagnostic techniques and novel therapeutics have improved the outcomes of affected newborns. This paper will review the historical aspects of PPHN and enable the reader to see how far we have come but also how far we have to go in conquering this unique disorder.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Seminars in Fetal and Neonatal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Goldsmith J.P.
        Overview and initial management of delivery room resuscitation.
        in: Martin R.J. Fanaroff A.A. Walsh M.C. Fanaroff and martin's neonatal-perinatal medicine. Diseases of the fetus and infant. eleventh ed. Elsevier, Philadelphia2020: 516-529
        • Walsh-Sukys M.C.
        • Tyson J.E.
        • Wright L.L.
        • et al.
        Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes.
        Pediatrics. 2000; 105: 14-20
        • Harvey W.A.
        Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus The Classics of Medicine Library.
        1978 (Birmingham, Alabama (The Keynes English Translation of 1928))
        • Cabrera E.
        • Borges S.
        • Novelo S.
        Electrocardiographic study of the persistence of the ductus arteriosus.
        Arch Inst Cardiol Mex. 1950; 20: 426-446
        • Keith J.D.
        • Forsyth C.
        Aortography in infants.
        Circulation. 1950; 2: 907-914
        • Lind J.
        • Wegelius C.
        Angiocardiographic studies in children.
        Adv Pediatr. 1952; 5: 154-194
        • Lind J.
        • Wegelius C.
        Human fetal circulation: changes in the cardiovascular system at birth and disturbances in the post-natal closure of the foramen ovale and ductus arteriosus.
        Cold Spring Harbor Symp Quant Biol. 1954; 19: 109-125
        • Burchell H.B.
        • Swan H.J.
        • Wood E.H.
        Demonstration of differential effects on pulmonary and systemic arterial pressure by variation in oxygen content of inspired air in patients with patent ductus arteriosus and pulmonary hypertension.
        Circulation. 1953; 8: 681-694
        • Eldridge F.L.
        • Hultgren H.N.
        • Wigmore M.E.
        The physiologic closure of the ductus arteriosus in newborn infants: a preliminary report.
        Science. 1954; 119: 731-732
        • Berglund G.
        • Karlberg P.
        • Lind J.
        Studies of the respiration and circulation during the neonatal period.
        Acta Paediatr Suppl. 1955; 44: 136-137
        • Prec K.J.
        • Cassels D.E.
        Dye dilution curves and cardiac output in newborn infants.
        Circulation. 1955; 11: 789-798
        • James L.S.
        • Rowe R.D.
        The patterns of response of pulmonary and systemic arterial pressures in newborn and older infants to short periods of hypoxia.
        J Pediatr. 1957; 51: 5-11
        • Herzenberg H.
        • Adams F.H.
        • Lind J.
        Studies of the effects of certain drugs on the pulmonary arterial and right ventricular pressure in children with congenital heart disease.
        Cardiologia. 1959; 35: 47-61
        • Corey Jr., J.H.
        • Waddell Jr., W.W.
        • Mitchell F.N.
        Premature infant mortality.
        J Pediatr. 1957; 50: 340-344
        • Rowe G.G.
        • Paul L.W.
        A case of abnormal cardiac position (levoposition).
        Circulation. 1959; 19: 750-752
        • Rudolph A.M.
        • Drorbaugh J.E.
        • Auld P.A.
        • Nadas A.S.
        • Smith C.A.
        • Hubbell J.P.
        Studies on the circulation in the neonatal period. The circulation in the respiratory distress syndrome.
        Pediatrics. 1961; 27: 551-566
        • Burnard E.D.
        • James L.S.
        Failure of the heart after undue asphyxia at birth.
        Pediatrics. 1961; 28: 545-565
        • Jegier W.
        • Blankenship W.
        • Lind J.
        • Kitchin A.
        The changing circulatory pattern of the newborn infant studied by the indicator dilution technique.
        Acta Paediatr. 1964; 53: 541-552
        • Stahlman M.
        Treatment of cardiovascular disorders in the newborn.
        Pediatr Clin. 1964; 11: 363-400
        • Stahlman M.T.
        Assessment and care of newborn problems.
        Listing Res Cardiovasc Field. 1964; 10: 259
        • Stahlman M.
        • Lequire V.S.
        • Young W.C.
        • Merrill R.E.
        • Birmingham R.T.
        • Payne G.A.
        • et al.
        Pathophysiology of respiratory distress in newborn lambs. Circulatory, biochemical, and pathological considerations.
        Am J Dis Child. 1964; 108: 375-393
        • Gersony W.M.
        • Duc G.V.
        • Sinclair J.C.
        “PFC” syndrome (persistence of the fetal circulation).
        Circulation. 1969; 40 ([Abst)]): S87
        • Peckham G.J.
        • Fox W.W.
        Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension.
        J Pediatr. 1978; 93: 1005-1010
        • Drummond W.H.
        • Gregory G.A.
        • Heymann M.A.
        • Phibbs R.A.
        The independent effects of hyperventilation, tolazoline, and dopamine on infants with persistent pulmonary hypertension.
        J Pediatr. 1981; 98: 603-611
        • Ward R.M.
        Pharmacology of tolazoline.
        Clin Perinatol. 1984; 11: 703-713
        • Wung J.T.
        • Stark R.I.
        • Hegyi T.
        • Driscoll J.M.
        • James L.S.
        CDP: a major breakthrough.
        Pediatrics. 1976; 58: 783-787
        • Bartlett R.H.
        • Roloff D.W.
        • Cornell R.G.
        • Andrews A.F.
        • Dillon P.W.
        • Zwischenberger J.B.
        Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study.
        Pediatrics. 1985; 76: 479-487
        • O'Rourke P.P.
        • Crone R.K.
        • Vacanti J.P.
        • Ware J.H.
        • Lillehei C.W.
        • Parad R.B.
        • Epstein M.F.
        Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study.
        Pediatrics. 1989; 84: 957-963
      1. UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation. UK collaborative trial group.
        Lancet. 1996; 348: 75-82
        • Tin W.
        • Lal M.
        Principles of pulse oximetry and its clinical application in neonatal medicine.
        Semin Fetal Neonatal Med. 2015; 20: 192-197
      2. Donn S.M. Neonatal and pediatric pulmonary graphics. Principles and clinical applications. Futura Publishing Co., Armonk, NY1998
        • Donn S.M.
        • Nicks J.J.
        • Becker M.A.
        Flow-synchronized ventilation of preterm infants with respiratory distress syndrome.
        J Perinatol. 1994; 14: 90-94
        • Sinha S.K.
        • Donn S.M.
        • Gavey J.
        • McCarty M.
        Randomised trial of volume controlled versus time cycled, pressure limited ventilation in preterm infants with respiratory distress syndrome.
        Arch Dis Child Fetal Neonatal Ed. 1997; 77: F202-F205
        • Pokora T.
        • Bing D.
        • Mammel M.
        • Boros S.
        Neonatal high frequency jet ventilation.
        Pediatrics. 1983; 72: 27-32
        • Kinsella J.P.
        • Clark R.H.
        High frequency oscillatory ventilation in pediatric critical care.
        Crit Care Med. 1993; 21: 174-175
        • Avery M.E.
        • Merritt T.A.
        Surfactant-replacement therapy.
        N Engl J Med. 1991; 324: 910-912
        • Ignarro L.J.
        • Buga J.M.
        • Wood K.S.
        • Byrns R.E.
        • Chaudhuri G.
        Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
        Proc Natl Acad Sci USA. 1987; 84: 9265-9269
        • Neonatal inhaled nitric oxide study group
        Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure.
        N Engl J Med. 1997; 336: 597-604
        • Roberts Jr., J.D.
        • Fineman J.R.
        • Morin 3rd, F.C.
        • Shaul P.W.
        • Rimar S.
        • Schreiber M.D.
        • et al.
        Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The inhaled nitric oxide study group.
        N Engl J Med. 1997; 336: 605-610
        • Davis M.D.
        • Donn S.M.
        • Ward R.M.
        Administration of inhaled pulmonary vasodilators to the mechanically ventilated neonatal patient.
        Pediatr Drugs. 2017; 19: 183-192
        • Roberts K.
        • Stepanovich G.
        • Bhatt-Mehta V.
        • Donn S.M.
        New pharmacologic approaches to bronchopulmonary dysplasia.
        J Exp Pharmacol. 2021; 13: 377-396
        • Gupta S.
        • Donn S.M.
        Assessment of neonatal perfusion.
        Semin Fetal Neonatal Med. 2020; 25: 101144-101149
        • de Boode W.P.
        • Singh Y.
        • Molnar Z.
        • Schubert U.
        • Savoia M.
        • Sehgal A.
        • et al.
        Application of neonatologist performed echocardiography in the assessment and management of persistent pulmonary hypertension of the newborn.
        Pediatr Res. 2018; 84: 568-577